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Maternal apo E genotype is a modifier of the Smith-Lemli-Opitz syndrome
  1. M Witsch-Baumgartner1,
  2. M Gruber1,
  3. H G Kraft1,
  4. M Rossi2,
  5. P Clayton3,
  6. M Giros4,
  7. D Haas5,
  8. R I Kelley6,
  9. M Krajewska-Walasek7,
  10. G Utermann1
  1. 1Department of Medical Biology and Human Genetics, Innsbruck Medical University, Austria
  2. 2Department of Paediatrics, Frederico II University, Naples, Italy
  3. 3Institute of Child Health and Great Ormond Street Hospital, London, UK
  4. 4Institute for Clinical Biochemistry, Barcelona, Spain
  5. 5University Children’s Hospital, Heidelberg, Germany
  6. 6Kennedy Krieger Institute and Dept of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, MD, USA
  7. 7Department of Medical Genetics, the Children’s Memorial Health Institute, Warsaw, Poland
  1. Correspondence to:
 Dr M Witsch-Baumgartner
 Department of Medical Biology and Human Genetics, Innsbruck Medical University, Schöpfstraße 41, 6020 Innsbruck, Austria;


Background: Smith-Lemli-Opitz syndrome (MIM 270400) is an autosomal recessive malformation and mental retardation syndrome that ranges in clinical severity from minimal dysmorphism and mild mental retardation to severe congenital anomalies and intrauterine death. Smith-Lemli-Opitz syndrome is caused by mutations in the Δ7 sterol-reductase gene (DHCR7; EC, which impair endogenous cholesterol biosynthesis and make the growing embryo dependent on exogenous (maternal) sources of cholesterol. We have investigated whether apolipoprotein E, a major component of the cholesterol transport system in human beings, is a modifier of the clinical severity of Smith-Lemli-Opitz syndrome.

Method: Common apo E, DHCR7, and LDLR genotypes were determined in 137 biochemically characterised patients with Smith-Lemli-Opitz syndrome and 59 of their parents.

Results: There was a significant correlation between patients’ clinical severity scores and maternal apo E genotypes (p = 0.028) but not between severity scores and patients’ or paternal apo E genotypes. In line with their effects on serum cholesterol levels, the maternal apo ϵ2 genotypes were associated with a severe Smith-Lemli-Opitz syndrome phenotype, whereas apo E genotypes without the ϵ2 allele were associated with a milder phenotype. The correlation of maternal apo E genotype with disease severity persisted after stratification for DHCR7 genotype. There was no association of Smith-Lemli-Opitz syndrome severity with LDLR gene variation.

Conclusions: These results suggest that the efficiency of cholesterol transport from the mother to the embryo is affected by the maternal apo E genotype and extend the role of apo E and its disease associations to modulation of embryonic development and malformations.

  • apo, apolipoprotein
  • DHC, dehydrocholesterol
  • DHCR7, Δ7-sterol reductase
  • SHH, sonic hedgehog homologue
  • 0, “null” mutations
  • 4L, mutations located in the 4th cytoplasmic loop
  • CT, mutations located in the C terminal region of the protein
  • TM, mutations located in transmembrane domains
  • apo E
  • cholesterol
  • DHCR7
  • Smith-Lemli-Opitz syndrome

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  • This work was supported by grant no T161 from the Austrian Science Fund (FWF) to MW-B, P-15480 GEN from the Austrian Science Fund to GU, grant no 4P05E09118 from the State Committee for Scientific Research of the Republic of Poland to MK-W and grant from “MIUR Rome, Italy, PRIN 2002 prot. 2002068222_003” to MR.

  • Conflicts of interest: none declared.

  • M Witsch-Baumgartner and M Gruber contributed equally to this work.